In 1959 the spontaneous production of autoantibodies was discovered in New Zealand (NZ) mice. Subsequent studies demonstrated a striking similarity of New Zealand Black mice to patients with idiopathic acquired hemolytic anemia and New Zealand Black x White F1 hybrids to humans with systemic lupus erythematosus. However, despite an extensive cataloguing of immunologic defects, the precise role of the thymus and spleen and their respective cell populations in the pathogenesis of both autoimmune and lymphoproliferative disease in these mice remains unclear. Over the past three years, our laboratory has generated, by selective husbandry and genetic testing, two unique animal models to help in the resolution of these issues. These models are germfree congenitally athymic (nude) NZB, NZW and NZB x NZW F1 mice and hereditarily asplenic (Dh/plus) NZB, NZW, and NZB x NZW F1 mice. Data accumulated thus far on these mutant mice, as well as analogous studies on murine thymic reticular tissue, suggest that multiple immunologic and thymic epithelial cell defects occur early in the life of NZ mice. These defects act at different levels to modify the clinical expression of disease. Although specific regulatory populations and autoantibodies are very important for disease manifestations, it is felt from observations of these mutant mice that premature loss of thymic suppressor cells and development of naturally occurring thymocytotoxic antibodies (NTA) are secondary products of disease. Nonetheless, NTA appears to play a major role in lymphoproliferative disease production. It is proposed herein over the next three years, to study our mutant NZ populations to extend our knowledge of lymphoid population interactions in the production of disease. These studies will be complemented by analogous observations on germfree B-cell depleted NZ mice. In this manner, it is hoped that changes in immunologic maturation, production of autoantibodies, and abnormalities within the environment of the thymus will lead to specific and successful manipulation of pathology.